Recent Progress in the Treatment of Thyroid Cancer: A Risk-Based ApproachSymposium Moderators:Dr June-Key ChungDr Young-Kee Shong

Welcome and introductionDr June-Key ChungProfessor of Nuclear Medicine Seoul National University Hospital, Korea

Programme

Welcome and introduction

Case Review: a risk-based approachDr Furio Pacini (Italy)Dr R. Michael Tuttle (US)

Audience Q&A Dr Young-Kee Shong (Korea)

Concluding remarks Dr Young-Kee Shong (Korea)

Luncheon served

Questions

A voting card is in your pack – this can be used to answer questions from the presenters

Q & A session – use the standing microphones

Case Review: a risk-based approachDr Furio PaciniProfessor of EndocrinologyUniversity of Siena, Italy

Clinical case

• A 45 year-old medical sonographer does a neck US on herself and finds abnormal looking paratracheal nodes. They are hypoechoic with multiple echogenic foci. The thyroid gland is normal.

• FNAC of one of the paratracheal nodes shows highly atypical cells and serum Tg in the aspirate is 480 ng/ml.

Clinical case

• The patient undergoes a total thyroidectomy plus bilateral central and right lateral neck dissection.

• Pathology: classical papillary thyroid cancer in the right lower pole (3 mm); four of six central nodes are + for classical papillary cancer; lymph nodes in the right lateral nodes normal.

• AJCC/UICC Stage I

• ATA risk: intermediate. ETA risk: high

Risk stratification ATA Guidelines

ATA Guidelines 2008. Thyroid 2009:19:1167-1214

Indication for RAI ablation (ATA)

ATA Guidelines 2008. Thyroid 2009:19:1167-1214

Low risk High risk

Intrathyroidal tumor(T1 >1 cm-T2), uni- or multifocal Aggressive histology No local or distant metastases

Possible indication

T3 Intrathyroidal or wiht minimal extrathyroidal invasion T4 Locoregional metastases Distant metastasesStrong indication

Very Low risk

Unifocal intrathyroidal tumor (≤1 cm) No aggressive histology No metastases

No indication

ETA Consensus 2006. Eur J Endocrinology 2006; 154: 787–803

ETA Consensus

Case 1

• The patient received 50 mCi of 131I after administration of rhTSH (0.9 mg i.m. for two consecutive days)

• Basal TSH: 0.2 mU/l, TSH after rhTSH: 156 mU/l

• Basal Tg <1.0 ng/ml, Tg after rhTSH: 2.1 ng/ml

• Urinary excretion: 120 mg/l, AbTg negative

• Post-therapeutic whole body scan: “uptake in the thyroid bed and two lateral nodes.”

Case

Post-therapeutic WBS: “uptake in the thyroid bed and in the right cervical region“

Case

• 12 months after ablation:

• rhTSH control diagnostic WBS: no uptake

• Neck ultrasound: negative

• Basal and stimulated Tg undetectable (<1 ng/ml)

• The patient is considered in remission.

Question for the audience:

• Is this patient still high risk?

A. Yes

B. No

Tuttle RM, et al. Thyroid 2010;20: 1341-9

PPV 95% CI NPV 95% CI PVE

ETA 0.384*° 0.355-0.407

0.913*° 0.878-0.941 19.1%

ATA 0.392*° 0.360-0.417

0.906*° 0.871-0.934 25.4%

DRS 0.728° 0.685-0.759

0.963° 0.944-0.977 62.1%

512 patients

* p>0.05; ° p<0.05Castagna MG, et al. Eur J Endocrinology 2011;165: 441–446

Question for the audience:

• What follow-up in this patient?

A. Basal serum Tg and neck US once a year

B. TSH-stimulated Tg

OUTCOME OF PATIENTS WITH TSH STIMULATED Tg 1ng/mL (Negative neck US)

• 219 patients• Mean follow-up:

15 years

• Neck lymph node recurrence at US: 1 (< 0.5%).

• TSH in the normal range (0.5-2.5 mU/L) in > 90%.

Cailleux, JCEM, 2000.

Excellent NPV of Tg/TSHNo clinical significance of low uptake in thyroid bed

• 315 patients • Mean follow-up:

12 years• Neck lymph node

recurrences at US: 2 (0.6%).

Pacini, JCEM, 2002.

Castagna MG, et al. Eur J Endocrinology 2011;165: 441–446

In patients with no evidence of disease:

• Risk of recurrence at 20 years < 0.5%

• The daily dose of LT4 may be decreased to achieve a serum TSH in the low-normal range

• Subsequent follow-up: clinical examination, serum Tg and TSH determination, neck US once a year

• Is there a need for further rhTSH-stimulated Tg?

NO NEED TO REPEAT rhTSH IN PATIENTS WITH UNDETECTABLE rhTSH STIMULATED Tg

CASTAGNA, JCEM, 2008

• 77 patients with no evidence of disease at 9-12 months. Repeated rhTSH + neck US at 2-3 years.

– 67 with undetectable rhTSH stimulated Tg: • at 2-3 years, 67 had undetectable rhTSH stimulated Tg

• neck US demonstrated neck recurrence in 1

– 10 with detectable rhTSH stimulated Tg: • at 2-3 years, 6 had undetectable rhTSH stimulated Tg

• 4 had detectable stimulated Tg

Castagna MG, et al. JCEM 2008; 93:76–81

• 203 DTC patients fulfilling the criterion of remission after initial therapy

• TSH-stimulated Tg repeated 5 years later

• 94.6% stimulated Tg <1-2 ng/ml: no recurrence

• 5.4% (11 pts) stimulated Tg >2 ng/ml (4.5-43 ng/ml):– 3: Lymph node mets detected by US– 5: mets detected by other imaging (2 in cervical

nodes, 1 in the mediastinum, 2 in the lungs)– 3: disease not found Rosario, PW, et al. Thyroid 2012;22:482-6

Application of the Risk Based Management Approach – decision-making with regard to RAI ablationDr R Michael Tuttle, MDProfessor of Medicine Memorial Sloan Kettering Cancer Center New York

Changing Paradigms in the Management of Thyroid Cancer

Increased EmphasisRisk of death

Risk of recurrenceRisk of persistent

diseaseRisk of failing initial

therapy

“Traditional Paradigm”One Size Fits All

Total thyroidectomyRAI remnant ablation

All with same follow up

“Risk Adapted Paradigm”

Management recommendations based

individualized risk assessment

It ain't what you don't know that gets you into trouble.

It's what you know for sure that just ain't so.

Words of wisdom attributed to Mark Twain

Changing management paradigms

What we know “for sure”

30% risk of recurrence(Over estimate the risk of recurrence?)

RAI ablation decreases recurrence by 50%(Over estimate the impact of RAI on

recurrence?)

Side Effects of RAI are mild and temporary(Under estimate the side effects of RAI?)

RAI ablation decreases the risk of death (Over estimate the impact of RAI on survival?)

RAI ablation is required for follow-up(Under estimate neck US and Tg without

ablation?)

Low RiskIntrathyroidal DTC

Intermediate RiskN1 disease,

minor extrathyroidal extensionvascular invasion,

or aggressive histology

High RiskGross extrathyroidal extensionincomplete tumor resection,

or distant metastases

Unifocal PMC (1-2%)

Multifocal PMC (4-6%)

Intrathyroidal 2-4 cm PTC (5-6%)

pN1, < 5 LN involved (4%)

pN1, > 5 LN involved (19%)

Clinical N1 (22%)

pN1, all LN < 0.2 cm (5%)

pN1, any LN > 3 cm (27%)

pT3 minor ETE (3-8%)

pT4a gross ETE (23-40%)

Risk stratification by category Risk stratification within categories*

Risk of Structural Disease Recurrence

*Manuscript in preparation,Randolph Thyroid 2012

FTC, extensive vascular invasion (30-55%)

Minimally invasive FTC (0-7%)

PTC, vascular invasion (16-30%)

32 yr old maleTotal thyroidectomy

1.9 cm unifocalIntrathyroidal PTC

No lymph nodes were sampled

2-3 months post-op: Tg 1 ng/mL

TSH was 1 mIU/mLTg Ab negative

Neck US is normal

First Example Patient

RAI AblationA. Yes B. No

32 yr old maleTotal thyroidectomy, 1.9 cm intrathyroidal

PTCRisk Without RRARecurrence 2-4%

Disease Specific Mortality < 1%Distant Metastases about 1%

Risks of RAIPermanent dry mouth 1-

2%Blocked tear duct 1%Second cancer < 1%

Potential Benefits of RAIFacilitate

Staging/Follow-up+/- Recurrence

No impact on mortality

Tilting the Balance Toward BenefitSelective Use

Lower administered activities (30 mCi)

rhTSH preparationUsing RAI as salvage therapy

Second Example Patient

• 22 year old female• Total thyroidectomy & left MRN dissection• 2.5 cm, multifocal, well differentiated PTC• 20/32 lymph nodes positive• No extrathyroidal extension• No vascular invasion

RAI AblationA. Yes B. No

22yr old femaleTotal thyroidectomy, 2.5 cm intrathyroidal PTC,

N1bRisk Without RRA

Recurrence 25-30%Disease Specific Mortality < 1%

Distant Metastases about 5-10%

Risks of RAIPermanent dry mouth 1-

2%Blocked tear duct 1%Second cancer < 1%

Potential Benefits of RAIFacilitate

Staging/Follow-up+/- Recurrence

No impact on mortality

Tilting the Balance Toward Benefit

Selective Use100 mCirhTSH?

What if her post-operative Tg was <0.2 ng/mL (TSH of 56 mU/L, no Tg antibodies)?

Unifocal PMC (1-2%)

Multifocal PMC (4-6%)

Intrathyroidal 2-4 cm PTC (5-6%)

pN1, < 5 LN involved (4%)

pN1, > 5 LN involved (19%)

Clinical N1 (22%)

pN1, all LN < 0.2 cm (5%)

pN1, any LN > 3 cm (27%)

pT3 minor ETE (3-8%)

pT4a gross ETE (23-40%)

Risk stratification by category Risk stratification within categories*

Risk of Structural Disease RecurrenceMy personal practice as of Nov 2012

FTC, extensive vascular invasion (30-55%)

Minimally invasive FTC (0-7%)

PTC, vascular invasion (16-30%)

Low RiskUsually no RAI

If given, 30 mCi rhTSH

High RiskRAI given

Probably withdrawal150 mCi

Intermediate RiskSelective use

rhTSH or withdrawal0 to 30 to 150 mCi depending on risk

*Manuscript in preparation,Randolph Thyroid 2012

New York City

Some points on Tg levelDr June-Key ChungProfessor of Nuclear Medicine Seoul National University Hospital, Korea

Assumption of the ideal tumor marker

All cancer cells express the tumor marker homogenously.

All cancer cells secrete the tumor marker into the blood relatively equally.

There is no change in the expression of tumor marker according to the patients and lesions.

There is no change in the expression of tumor marker according to differentiation or progression of cancer.

Facts of serum thyroglobulin

660 kDa dimeric protein, > 20 epitopesdifferent antibodies -> different concentrations in

commercial kits Different nature

CEA, AFP: increase associated with carcinogenesis Tg: normal component

Immunostaining results showed that Tg expression was heterogenous and variable in PTC, and related to cellular differentiation in FTC.

The expression of Tg might decrease in metastatic tissue of lymph node. Almost all cancers in Korea are PTCs, which often are de-differentiated

and negative in Tg expression. In thyroid cancer cells, Tg molecule can be modified inhibiting secretion

to the blood, or cannot be measured by some kits.

Item QC Conc.CV in 2012 (%)

Jan Feb Mar Apr May Jun Avr

Tg

C-1 2.45 15.8 12.8 11.6 17.2 9.4 14.6 13.6

C-2 27.8 7.7 12.2 10.6 11.9 9.0 11.3 10.5

C-3 70.1 7.1 8.7 9.0 10.4 8.3 9.5 8.8

T3

C-1 101 7.5 6.3 3.0 3.7 3.2 2.6 4.4

C-2 157 6.5 2.4 2.0 1.7 1.8 1.5 2.7

C-3 255 6.9 3.4 2.9 2.2 1.2 2.1 3.1

T4

C-1 5.86 13.8 8.7 3.0 2.9 3.6 4.5 6.1

C-2 9.98 10.4 5.3 2.5 3.4 2.8 2.2 4.4

C-3 15.8 7.9 4.7 2.0 2.0 1.7 2.7 3.5

CA 125

C-1 30.6 6.7 1.5 3.5 4.0 5.5 5.2 4.4

C-2 98.3 4.9 3.6 3.1 2.8 4.0 4.0 3.7

C-3 260 2.4 2.5 3.7 4.3 5.6 4.5 3.8

AFP

C-1 9.7 5.5 5.4 6.5 5.0 4.9 4.7 5.3

C-2 70.9 4.2 4.0 4.0 5.7 4.5 4.0 4.4

C-3 177 4.5 5.8 5.1 6.3 5.6 4.6 5.3

External QC data in Korea

Metastatic lymph nodes 15.93±8.42 mg/g Hurthle adenoma

1969.54±1601.11 mg/g Papillary thyroid carcinoma 206.02±476.56

mg/g Follicular thyroid carcinoma 83.76±24.33 mg/g Anaplastic thyroid carcinoma 1.63±0.48 mg/g Normal

50-100 mg/g A. Czarnywojtek.Archivum Immunologiae et Therapiae

Experimentalis, 2002, 50, 143-148

Thyroglobulin Content in Thyroid Tissue

Staining intensities Value (%)

Thyroglobulin (n=47)

0 0 (0%)

1 7 (15%)

2 30 (64%)

3 10 (21%)

Immunohistochemistry results of Thyroglobulin in Papillary cancer

J-K Chung and H Min. KTA 2012.

Cytoplasm Membrane

Location of Thyroglobulin in Cancer tissue

Poorly differentiated carcinoma

Heterogenous Expression of Tg

A

C

B

A: Primary papillary microcarcinoma(x200)

B: Tg immunostaining of primary tumor, strong positive

(x400)

C: Tg immunostaining of lymph node, focal positive (x200)

• Subject- Differentiated thyroid carcinoma- ’01.1~’04.12 post-Therapy I-131 WBS (≥ 30 mCi)- Consecutive 824 patients

• Tg negative/I-131 WBS positive group (TgFN)- Tg ≤ 2 ng/mL (Tg-plus, BRAHMS, Germany)- Tg Ab ≤ 100 U/mL (HENNINGtest® anti-Tg, BRAHMS,

Germany) TSH-stimulation state (TSH ≥ 30 μIU/ml)

- I-131 WBS: remnant and/or functioning metastasis

• Tg positive/I-131 WBS positive group (TgP)- Tg > 2 ng/mL- I-131 WBS: remnant and/or functioning metastasis

Recurrent/metastatic thyroid carcinoma: false negative Tg, positive I-131 scan

Park EK, Chung JK et al, Eur J Nucl Med Mol Imaging, 2009;36:172-9

F/55

Tg negative/I-131 positive case

TSH 89.4Tg <1.0 TgAb <25

Tg negative/I-131 positive case

M/17 TSH 195 Tg <1.0 TgAb <25

*59 excluded

TgAb(-) : 255 (31%)TgAb(-) : 255 (31%)

Metastasis:128

Metastasis:128

Remnant: 203

Remnant: 203

Metastasis:52 (6.3%)

Metastasis:52 (6.3%)

I-131 WBS: 824 I-131 WBS: 824

WBS(-): 72 WBS(+): 752

Tg(+): 328 Tg(-): 365

TgAb(+): 110

TgP vs TgFN

*p<0.001

Metastatic site TgP TgFN

Cervical/Mediastinal LN

91 (71.1%)45 (86.5%)

Lung 25 (19.5%) 6 (11.5%)

Bone 11 (8.6%) 1 (2.0%)

Brain 1 (0.8%) 0 (0%)

Total 128 52

TSH 219 Tg <1.0, Tg Ab<25

2006-12-19 I-131 200 mCi

2006-6-22 I-131 200 mCi

2005-12-17 I-131 200 mCi

TSH 158 Tg <1.0, Tg Ab<25

TSH 212 Tg <1.0, Tg Ab<25

2005-8-27 I-131 30 mCi

TSH 88 Tg 3.3, Tg Ab<60

Audience Q&APanel discussionDr Young-Kee ShongProfessor, Department of Internal Medicine, Endocrinology and MetabolismAsan Medical Center, Seoul

Concluding remarks

Dr Young-Kee ShongProfessor, Department of Internal Medicine, Endocrinology and MetabolismAsan Medical Center, Seoul

Summary

An individualised risk stratification approach is an emerging concept to guide initial therapy and follow up

Risk should be re-assessed at every follow up to guide further intervention and follow up

Importance of measuring Tg and TgAb with the same assay over timePlease join us for luncheon in the Restaurant

(where breakfast is served)